The goal of this revised program project is to study cell cycle checkpoint control in the context of the potential for therapeutic intervention. There are three sub-themes: 1) a mechanism and signaling of the DNA damage checkpoints; 2) drug and radiation sensitivity; and 3) apoptosis. This application bring together a group of five basic scientists and clinician- scientists from four departments at the University of Pennsylvania and the Fox Chase Cancer Center. This group represents diverse disciplines involved in oncology, pathology, genetics and molecular and cellular biology. Each member of the group has a strong and established track record in cell cycle research. The proposed program project builds on established interactions and collaborations between the laboratories of each of the scientists. The underlying theme of the project is to understand the molecular pathways for checkpoint control and their relationship to drug and radiation sensitivity. Dissection of the components of these pathways may lead to their exploitation in a clinical setting where drug and radiosensitivities of tumors and normal tissues can be manipulated. The mixture of basic and clinical scientists represented by this project is essential for the integration and focusing on their research efforts on the mechanism by which cells respond to DNA damage. The advantage of having a highly focused group will result in an enhanced "large picture" of the cell's response. The working group involved in the project will facilitate the placement of finding from each laboratory into the context of the overall theme. This will stimulate ideas, and the free flow of materials and information will expand the boundaries of the individual groups There are five proposed projects plus three cores from which all the investigators will draw. The ultimate result of the project will be a better understanding of now radio-therapy and chemotherapy may integrate knowledge of cell cycle checkpoints into the development of new treatment strategies.